Cytokines represent a large number of secreted proteins that regulate cell growth and differentiation. These factors are especially important in regulating immune and inflammatory responses, regulating lymphoid development and differentiation. Cytokines also regulate immune homeostasis, tolerance, and memory. Not surprisingly, cytokines are critical in the pathogenesis of autoimmune diseases such as rheumatoid arthritis, systemic lupus erythematosus, inflammatory bowel disease and psoriasis. Understanding the molecular basis of cytokine action provides important insights into the pathogenesis of immune-mediated disease and offers new therapeutic targets. We discovered Jak3, a kinase essential for signaling by cytokines that bind the common gamma chain, gc (IL-2, IL-4, IL-7, IL-9, IL-15 and IL-21). We found that mutation of Jak3 results in a primary immunodeficiency disorder termed severe combined immunodeficiency (SCID). We have a clinical protocol that allows us to evaluate patients with suspected Jak3 deficiency. No new patients were enrolled this year. Recent work by NIH scientists has revealed that another primary immunodeficiency syndrome, Job's or Hyperimmunoglobulin E syndrome is due to STAT3 mutations. Based on our studies in the mouse, we investigated if mutations of STAT3 in humans are associated with impaired Th17 differentiation. We found this to be the case in patients with Job's syndrome. Mutations of STAT3 underlie hyper-IgE syndrome (HIES), but deciphering STAT3s role in pathogenesis has been hampered by the lethality associated with germline deletion of Stat3. Furthermore, the mechanisms responsible for IgE hyperproduction are unknown. We show that transgenic mice expressing a HIES-Stat3 allele recapitulate aspects of HIES, including elevated serum IgE. Mutant B cells display increased Ig germline transcription and switch recombination upon ex-vivo activation, demonstrating the hyper-IgE defect is B cell intrinsic. At present, we are dissecting the relative roles of STAT3 in hematopoietic versus stromal cells. Using these mice, we are performing bone marrow transplantation experiments. These results may have important implications for patients with HIES. We have also employed new technology to begin to define STAT3 targets genome-wide. Specifically, we have used chromatin immunoprecipitation and massive parallel sequencing to comprehensively enumerate STAT3 target genes in Th17 cells. We found that STAT3 bound to multiple genes involved in Th17 cell differentiation, cell activation, proliferation, and survival, regulating both expression and epigenetic modifications. Thus, STAT3 orchestrates multiple critical aspects of T cell function in inflammation and homeostasis.